Natural Killer (NK) cells are a critical component of the host innate immune response to a variety of viruses, fungi, parasites, bacteria and certain tumors. The ability of NK cells to lyse targets does not depend on prior sensitization and their activity is not MHC restricted. Upon activation, NK cells release cytokines and chemokines that induce inflammatory responses, modulate hematopoeisis, control monocyte and granulocyte cell growth and function, and influence the type of adaptive immune responses that follow. In HIV-1 infection, the non-specificity of NK cell activity might be an important component of the antiviral activity observed during the adaptive immune response. Given the recent understanding of the complex array of inhibitory and activating receptors on the surface of NK cells that modulate their function, we examined the effect of HIV-1 infection on this balance of inducing and inhibitory NK receptors. We found that the surface expression of certain inhibitory NK receptors, particularly killer-immunoglobulin-like receptors (KIRs), was either normal or up-regulated while that of natural cytotoxicity receptors (NCRs), was downregulated on freshly isolated and/or activated NK cells in patients with HIV plasma viremia. In addition, we demonstrated that alterations in expression of iNKRs and NCRs in viremic patients were strongly associated with impaired NK lysis of HIV-infected cells. The decrease in function was not a result of direct infection of NK cells. Moreover, we demonstrated that neither freshly isolated nor activated NK cells had detectable levels of HIV DNA. Following suppression of plasma HIV RNA by HAART, the surface expression of these NK receptors and the function of these cells were normalized. We further identified a unique subset of CD56-/CD16+ NK cells that are expanded in viremic HIV-1 positive patients. In contrast, aviremic HIV-infected individuals treated with HAART for more than two years displayed an NK cell surface phenotype similar to that of normal individuals. Indeed, the majority of NK cells in aviremic patients were CD56+/CD16+, while only a minor subset was characterized by the CD56-/CD16+ phenotype. In addition, the ability to kill the NK-susceptible K562 erythroleukemia cell line was clearly reduced in NK cells from viremic patients, while the mean cytolytic activity of NK cells from HAART-treated aviremic patients was only slightly reduced as compared to that of normal controls. It has been reported that levels of TNF-a are elevated in the plasma of HIV-infected individuals and TNF-a has recently been shown to downregulate NKp30 and NKG2D in vitro. Therefore, we investigated the capability of NK cells to secrete TNF-a in culture after 6 hours (freshly isolated) and 6 days in culture with rIL-2 (activated).in viremic and aviremic HIV-infected individuals as well as in healthy donors We did not find any differences in secretion of TNF-a in the supernatant of NK cultures among the three cohorts of subjects. Thus, it is unlikely that the decrement in NKp30 expression that was observed in HIV-infected patients is due to a TNF-a-dependent autocrine mechanism. In summary, our investigations into the aberrant function of NK cells in HIV pathogenesis are revealing important clues concerning the physiologic balance of NK receptor expression, cytolytic activity, and the integrity of the innate immune system.